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Will the monkeypox virus become more dangerous?

A few years ago, researchers scoured the remains of 1867 people who lived between 30,000 and 150 years ago for genetic traces of variola, the virus that causes smallpox. In the teeth and bones of four Northern Europeans from the Viking era, they found enough DNA to reconstruct entire variola genomes. The sequenced viruses weren’t direct ancestors of the feared variola strain that was eradicated in the second half of the 20th century. But they may hold a clue to how smallpox became so deadly.

Over the span of 350 years, the Viking virus lost several genes, the researchers reported in a 2020 paper in Science. Researchers had seen this pattern before. The modern smallpox virus also lost several genes in the recent past, although as a result of different mutations. Seeing it twice “suggests that the loss of the genes was not an accident,” says poxvirologist Antonio Alcamí of the Severo Ochoa Center of Molecular Biology in Madrid. “It was selected for.” Alcamí thinks the losses may have made variola more virulent, resulting in its 30% mortality rate. In the past, smallpox may have been a “widespread mild disease,” he wrote in a commentary accompanying the paper.

Now, some scientists are wondering: Could something like this happen again?

Since May, a far less lethal cousin of variola, the monkeypox virus, has been spreading around the globe, giving the virus unprecedented opportunities to change and adapt to the human population. Will it evolve to become more contagious or cause more severe disease?

Nobody knows, but recent history with SARS-CoV-2 offers a sobering lesson. After emerging in Wuhan in late 2019, that virus first spawned a series of variants that could spread much faster than their progenitors and then evolved further to evade human immunity. Its tricks surprised even some scientists who have long studied viral evolution. SARS-CoV-2 showed that “if a novel virus is coming into a space in which there isn’t immunity, rapid adaptation can happen,” says Aris Katzourakis, an evolutionary virologist at the University of Oxford.

Monkeypox could present humanity with equally unpleasant surprises. In July, researchers in Berlin published a preprint analyzing the genome sequences of virus found in the lesions of 47 monkeypox patients. In addition to many small changes, they found one virus in which an entire gene was duplicated and four others were simply gone. The paper’s last paragraph almost read like a warning: “The consequence of changes in poxvirus genes whose products are no longer required in a new host or otherwise altered context is unpredictable,” the authors said. “The [monkeypox virus] phenotype we have known for the last 64 years may not resemble near-future human” monkeypox.

Many researchers say we shouldn’t worry too much yet. Geoffrey Smith, a poxvirologist at the University of Cambridge, doubts the monkeypox virus will readily turn into a much more virulent version. Poxviruses’ massive genomes are known to evolve at a sluggish pace, and they don’t adapt easily to elude immunity, as SARS-CoV-2 does so masterfully. And SARS-CoV-2 is a wildly contagious respiratory pathogen that infected hundreds of millions in its first year in the human population; monkeypox is spreading mostly among men who have sex with men, and only about 60,000 cases have been reported so far, so it has much less opportunity to evolve.

That could change, however. One “bad scenario,” says Bernard Moss, a veteran poxvirus researcher at the U.S. National Institute of Allergy and Infectious Diseases, is that the virus evolves to replicate faster in humans. That would allow it to infect more people, which would in turn speed up its evolution, potentially making it still more adept at infecting people.

For now, the monkeypox virus is not very good at infecting humans. It is a generalist that appears to thrive in a range of animal species—most of them rodents—in sub-Saharan Africa. From time to time the virus has spilled over into people, who have sometimes infected a few others. Although outbreaks have grown more frequent in recent years, they have typically been small. After each emergence the virus apparently disappeared again from the human population.

This time around is different, as monkeypox has continued to spread from person to person in a global outbreak. “We’ve never seen this virus with such an opportunity to adapt to humans before,” says Terry Jones, a computational biologist at Charité University Hospital in Berlin and one of the authors of the July preprint.

Viral family tree

Mutations seen in monkeypox samples allow researchers to trace the roots of the current outbreak, which began in Nigeria. The virus was exported to other countries several times and eventually spread around the world. Because a human protein, APOBEC3, likely introduced many of the mutations, they can also show how long the virus has been spreading in people.

(Graphic) C. Bickel/Science; (Data) Data made available on GenBank by NCDC and others

Reported cases are going down in many Western countries—most likely as a result of behavioral changes and vaccination—and public health officials in Europe are already talking about eliminating the virus in the region. But infections are still on the rise elsewhere in the world. In many places vaccines are unavailable, or people at risk either lack information about how to avoid infection or fear asking for it, because gay sex is criminalized.

“I don’t think [monkeypox] will cause massive numbers of infections, but it will stay there and it will be difficult to eradicate,” Alcamí says. “Decision-makers have to realize that this is not going away anytime soon,” adds Christian Drosten, a virologist at Charité and a co-author of the July preprint.

Science can’t do more than hint at how the virus might evolve as it continues to circulate. One reason is that research interest in poxviruses has dwindled after the worldwide smallpox eradication campaign ended in triumph in 1980. “I always had to start my talks by almost apologizing for working on poxviruses,” Alcamí says.

Evolutionary virologists have instead concentrated on the influenza virus, HIV, and other small viruses whose genomes consist of RNA. Poxviruses, by contrast, are made of DNA, and are much larger and more complex. With roughly 200,000 nucleotides and 200 genes, the monkeypox genome is more than 20 times the size of HIV’s. It’s not clear what many of those genes do, Moss says, let alone how they interact with each other or how changes in any of them might affect their impact on humans.

A rat with large, long upright ears on a forest floor.
A squirrel perched on a tree branch. It is mostly brown, with a white stomach and a wide darker brown stripe down its back.
The animal hosts of the monkeypox virus remain unknown, but many rodent species in Africa seem able to carry it, including the African pouched rat (Cricetomys emini, top) and the fire-footed rope squirrel (Funisciurus pyrropus, bottom).(Top to bottom) Christian Ziegler/Minden Pictures; David Hosking/Minden Pictures

Moss has been trying for years to figure out the crucial difference between two variants of monkeypox virus: clade 2, which until recently was found only in West Africa and is now causing the global outbreak, and clade 1, believed to be much deadlier, which has caused outbreaks in the Democratic Republic of Congo for many decades. He’s found that clade 1 virus can kill a mouse at levels 1000 times lower than those needed with clade 2. To find out why, Moss and his colleagues swapped dozens of clade 2 genes, one at a time, into clade 1 virus, hoping to see it become less deadly, but with no luck so far. Now, they are planning to try the opposite, endowing clade 2 virus with genes from its deadlier relative.

One thing is clear, however: Poxviruses mutate slowly compared with RNA viruses. “Their genomes are pretty stable and don’t change quickly,” Smith says. And although poxviruses have ways of tricking the immune system, they don’t change their surface proteins to escape immunity, as SARS-CoV-2 does. An infection with smallpox, if you survived it, provided immunity for life, and the vaccines remained very effective right until the end of the eradication campaign. That, too, offers some hope that monkeypox won’t transform into a bigger threat.

Researchers around the world are now mining monkeypox genomes from recent patients to learn how the virus has evolved so far. Getting high-quality sequences is harder and more expensive than it is for SARS-CoV-2, not just because the monkeypox genome is so vast but also because crucial regions near its ends can be full of repetitions or deletions that can trip up researchers when they assemble sequences. “Handling these genomes is more complex than the RNA viruses,” says Richard Neher, a computational biologist at the University of Basel. “It will be more important than with SARS-CoV-2 that people share their raw data.”

Still, the work is already yielding some results. When researchers compared recent genomes from the current monkeypox outbreak with older sequences, like one isolated from a traveler from Nigeria in the United Kingdom in 2019, they quickly noticed two interesting things. The genomes had more point mutations than expected after only a few years, and many of them followed the same pattern, with the nucleotide combination guanine-arginine changing to arginine-arginine, or thymine-cytosine changing to thymine-thymine.

Head and torso of a partially unearthed human skeleton.
Viral DNA found in Viking skeletons suggested the loss of some genes may have made the smallpox virus more virulent. B. Mühlemann et al., Science (2020)

Those mutations are probably traces of an ongoing fight between the virus and the human immune system. A human protein called APOBEC3 acts as a cellular defense mechanism by introducing errors into the viral genome as it gets copied, and the changes spotted in the monkeypox genomes are its signature. “Clearly, it’s not sufficient to stop the virus replicating,” says molecular evolutionary biologist Andrew Rambaut of the University of Edinburgh.

In the long term, though, the mutations could make the virus less fit as they accumulate—or one of them could happen to benefit the virus. Still, “My hunch is that this is probably not going to be very important from an evolutionary point of view,” Rambaut says.

What these mutations can do is give researchers a clock to determine how long ago monkeypox began to circulate in humans. Comparing genomes from different time points suggests the virus is currently adding about six APOBEC3-related changes per year, says Áine O’Toole, an evolutionary biologist at Edinburgh. A family tree of virus genomes from the current outbreak suggests viruses circulating in Nigeria in late 2017 already carried nine APOBEC3-type mutations, which would mean the virus jumped into humans sometime in early 2016, about a year and a half before the outbreak was recognized in Nigeria (see graphic, above). The analysis also suggests the virus has been continuously circulating in humans since then.

But poxviruses can evolve in other, more drastic ways than single nucleotide changes. They “do a lot of evolutionary off-roading,” says Nels Elde, a virologist at the University of Utah who turned to monkeypox after many years of studying vaccinia, the weakened poxvirus that served as a smallpox vaccine. Elde explains that poxvirus genomes usually consist of a central region with about 100 genes that are mostly involved in creating new copies of the virus, and terminal regions with another 100 or so genes that interact with the host, for instance to counteract immune defenses.

Those terminal genes appear to be a key site of evolution. Generalist poxviruses that infect many different hosts, including monkeypox and cowpox, tend to have more genes in the terminal regions, whereas smallpox, which specializes in infecting humans, has many fewer. Most researchers believe smallpox evolved from a rodent poxvirus that jumped to humans. Over time, gene losses such as those seen in the Viking virus may have made it more deadly, says molecular evolutionary geneticist Hendrik Poinar of McMaster University.

Black and white photograph. A young person rolls up their sleeve so that a doctor can place a needle against their upper arm, while a nurse watches, holding a piece of gauze. All three are intently focused on where the needle meets the patient's arm.
Black and white photograph. A New York City block, with two long queues of people stretching down the street and around the corner.
A teenage boy receives the smallpox vaccine in Gasport, New York, in 1938 (first image), and people line up for vaccination in New York City (second image). The eradication of smallpox, completed in 1980, caused research interest in poxviruses to dwindle. (First image) Bettmann Archive; (Second image) Harry Chamberlain/FPG/Hulton Archive/Getty Images

“Smallpox goes from what we think is actually a very avirulent form, to repeated gene inactivation to really damn nasty until we eradicate it,” Poinar says. Based on the 2020 Science paper and his own work on a variola genome from a 17th century child mummy, Poinar believes this happened sometime between the fourth and the 15th century.

How the loss of genes would have made variola more virulent is not exactly clear, however. Simply having a smaller genome might make the virus more adept at replicating in human cells, says Eugene Koonin, a researcher at the U.S. National Center for Biotechnology Information. “Making the replication, say, 10% faster is a very big deal,” Koonin says. “Once it happens, this variant outgrows the competitors very, very quickly.”

The terminal genes can also evolve through another mechanism. They often get duplicated during viral replication, which can help the virus in two ways. The additional copies enable it to quickly produce much more of a needed protein, and they increase the chance that at least one copy of the gene will undergo a beneficial mutation. The “improvement” can make the other copies redundant, and they may be lost, shortening the genome. Elde, who studied the mechanism in the vaccinia virus, calls it a “genomic accordion.”

Those changes could affect how the virus interacts with the human immune system, weakening its defenses, for example. But trying to predict the effects of specific mutations is like “shitty weather forecasting,” Elde says: “We have some patterns and some predictions we can make, but we really can’t stand solidly behind them because there’s a weather system that has massive variables spinning all around.”

Since they posted the preprint in July, Drosten’s lab has been studying the virus isolated from a patient in Berlin that had deleted and duplicated genes. As-yet-unpublished results are unsettling: “In cell culture it shows a clear difference, replicating a lot faster,” Drosten says. “We should not overinterpret that,” he cautions, because findings in the laboratory do not necessarily translate into an advantage for the virus in the real world. “But I find it remarkable that this virus already shows a difference in cell culture.”

If the virus had a real-world advantage but it simply did not transmit onward, then humanity may have been “just lucky,” Jones says—“this time.” He sees the current outbreak as a race between the monkeypox virus and humanity: “The virus is trying to adapt to humans and humans are trying to get rid of the virus,” he says. “Who’s going to get the upper hand? In the long term, I would put my money on the virus.”

Whatever comes next, the epidemic offers researchers an unexpected chance to watch a poxvirus evolve in real time. “We’re all kind of taking the clues, piecing it together, and hoping that this also is an opportunity to move science forward,” Elde says. “But I’m rooting for us, I’m rooting for the humans. … I want to learn how these viruses operate, and then use that information so that we can have some control over this.”

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